Steroid hormones, such as the estrogens and the androgens, represent an important class of clinically administered compounds. Estrogens are used extensively for replacement therapy, treatment of hypogonadism, and contraception. The androgens, and particularly testosterone, are used in replacement therapy, treatment of gynecologic disorders, as protein anabolic agents, and as metabolic stimulators.
When administered orally, testosterone is readily absorbed but is rapidly degraded by the liver so that only insignificant amounts reach the systemic circulation. When administered intramuscularly, testosterone is promptly absorbed from the injection vehicle, metabolized and excreted, making it difficult to achieve sustained, effective plasma levels.
Modified forms of testosterone have been developed for intramuscular use which are more soluble in the injection vehicle and are more slowly absorbed from the site of injection. The depot of drug thus provides a more sustained delivery of drug to the circulation. However, in many cases, injection is an undesirable form of drug administration due to its invasive nature, predisposition of the administration site to infection, and the potential painfulness of the procedure. Additionally, injection causes an initial high plasma level of drug which steadily decreases until the next injection.
An alternative which overcomes many of these difficulties is to administer such compounds transdermally. However, transdermal administration is often hampered by the fact that the skin is an efficient barrier to the ingress of materials. Very few therapeutic agents penetrate the skin at rates which allow the delivery of therapeutically effective amounts of drug.
Although many chemical penetration enhancers have been identified which may increase a compound's ability to penetrate the skin, the process of selecting a suitable enhancer system is often long and laborious, and many times unsuccessful. Many penetration enhancers also cause skin irritation, especially with prolonged exposure times. Some skin enhancing compounds, such as dimethyl formamide and dimethyl sulfoxide, may present potential toxicological complications.
Iontophoresis is a process which causes increased penetration of ionized compounds into the skin by use of an electrical gradient. Unfortunately, many of the drawbacks associated with transdermal administration also apply to iontophoresis. Additionally, delivery by iontophoresis is limited to compounds having readily ionizable groups.
Thus, it is desirable to provide a method for administering uncharged steroid hormones, such as the 17-hydroxy sterols, which allows delivery of therapeutically effective levels of drug, avoids excessive degradation of the active compound by the liver, avoids invasive routes of administration, and does not rely on the presence of potentially irritating or toxic skin permeation enhancing compounds.